Category Archives: Dolor

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Cannabinoids in Pain Management and Palliative Medicine.

Category : Dolor

Cannabinoids in Pain Management and Palliative Medicine.

Dtsch Arztebl Int. 2017 Sep 22;114(38):627-634

Authors: Häuser W, Fitzcharles MA, Radbruch L, Petzke F

Abstract
BACKGROUND: There are conflicting interpretations of the evidence regarding the efficacy, tolerability, and safety of cannabinoids in pain management and palliative medicine.
METHODS: We conducted a systematic review (SR) of systematic reviews of randomized controlled trials (RCT) and prospective long-term observational studies of the use of cannabinoids in pain management and palliative medicine. Pertinent publications from January 2009 to January 2017 were retrieved by a selective search in the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, and Medline. The methodological quality of the SRs was assessed with the AMSTAR instrument, and the clinical relevance of quantitative data syntheses was assessed according to the standards of the Cochrane Collaboration.
RESULTS: Of the 750 publications identified, 11 SRs met the inclusion criteria; 3 of them were of high and 8 of moderate methodological quality. 2 prospective long-term observational studies with medical cannabis and 1 with tetrahydrocannabinol/cannabidiol spray (THC/CBD spray) were also analyzed. There is limited evidence for a benefit of THC/CBD spray in the treatment of neuropathic pain. There is inadequate evidence for any benefit of cannabinoids (dronabinol, nabilone, medical cannabis, or THC/CBD spray) to treat cancer pain, pain of rheumatic or gastrointestinal origin, or anorexia in cancer or AIDS. Treatment with cannabis-based medicines is associated with central nervous and psychiatric side effects.
CONCLUSION: The public perception of the efficacy, tolerability, and safety of cannabis-based medicines in pain management and palliative medicine conflicts with the findings of systematic reviews and prospective observational studies conducted according to the standards of evidence-based medicine.

PMID: 29017688 [PubMed – in process]

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Is cannabis an effective treatment for joint pain?

Category : Dolor

Is cannabis an effective treatment for joint pain?

Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 107(5):59-67

Authors: Miller RJ, Miller RE

Abstract
Cannabis has been used to treat pain for thousands of years. However, since the early part of the 20th century, laws restricting cannabis use have limited its evaluation using modern scientific criteria. Over the last decade, the situation has started to change because of the increased availability of cannabis in the United States for either medical or recreational purposes, making it important to provide the public with accurate information as to the effectiveness of the drug for joint pain among other indications. The major psychotropic component of cannabis is Δ9-tetrahydrocannabinol (THC), one of some 120 naturally occurring phytocannabinoids. Cannabidiol (CBD) is another molecule found in herbal cannabis in large amounts. Although CBD does not produce psychotropic effects, it has been shown to produce a variety of pharmacological effects. Hence, the overall effects of herbal cannabis represent the collective activity of THC, CBD and a number of minor components. The action of THC is mediated by two major G-protein coupled receptors, cannabinoid receptor type 1 (CB1) and CB2, and recent work has suggested that other targets may also exist. Arachidonic acid derived endocannabinoids are the normal physiological activators of the two cannabinoid receptors. Natural phytocannabinoids and synthetic derivatives have produced clear activity in a variety of models of joint pain in animals. These effects are the result of both inhibition of pain pathway signalling (mostly CB1) and anti-inflammatory effects (mostly CB2). There are also numerous anecdotal reports of the effectiveness of smoking cannabis for joint pain. Indeed, it is the largest medical request for the use of the drug. However, these reports generally do not extend to regulated clinical trials for rheumatic diseases. Nevertheless, the preclinical and human data that do exist indicate that the use of cannabis should be taken seriously as a potential treatment of joint pain.

PMID: 28967368 [PubMed – in process]

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Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis.

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Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis.

Pain Med. 2016 Jun;17(6):1145-54

Authors: Russo M, Naro A, Leo A, Sessa E, D’Aleo G, Bramanti P, Calabrò RS

Abstract
OBJECTIVE: The aim of our study was to better investigate the role of Sativex(®) in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment.
SETTING: Pain is a common symptom of MS, affecting up to 70% of patients. Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results. Clinical pain assessment in MS is very difficult, and more objective tools are necessary to better quantify this symptom and its potential response to the treatments.
SUBJECTS AND METHODS: We enrolled 20 MS patients (10 with and 10 without neuropathic pain), who underwent a specific clinical (such as visual analog scale) and neurophysiological assessment (by means of laser-evoked potentials and transcranial magnetic stimulation), before and after 4 weeks of Sativex administration.
RESULTS: One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life. Interestingly, such effects were paralleled by an increase of fronto-central γ-band oscillation and of pain-motor integration strength.
CONCLUSIONS: Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.

PMID: 26764336 [PubMed – indexed for MEDLINE]

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Comparison of cannabinoids with known analgesics using a novel high throughput zebrafish larval model of nociception.

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Comparison of cannabinoids with known analgesics using a novel high throughput zebrafish larval model of nociception.

Behav Brain Res. 2017 Sep 18;:

Authors: Ellis LD, Berrue F, Morash M, Achenbach JC, Hill J, McDougall JJ

Abstract
It has been established that both adult and larval zebrafish are capable of showing nociceptive responses to noxious stimuli; however, the use of larvae to test novel analgesics has not been fully explored. Zebrafish larvae represent a low-cost, high-throughput alternative to traditional mammalian models for the assessment of product efficacy during the initial stages of drug development. In the current study, a novel model of nociception using zebrafish larvae is described. During the recovery from an acute exposure to low levels of acetic acid, larvae display innate changes in behaviour that may be indicative of nociception. To assess the usefulness of this model for testing potential analgesics, three known synthetic pain medications were assessed (ibuprofen, acetaminophen and tramadol) along with three naturally occurring products (honokiol, tetrahydrocannabinol and cannabidiol). When the effect of each compound on both the acetic acid recovery and control activity was compared there appeared to be both similarities and differences between the compounds. One of the most interesting effects was found for cannabidiol which appeared to oppose the activity change during the recovery period of AA exposed larvae while having a nominal effect on control activity. This would appear to be in line with current research that has demonstrated the nociceptive properties of cannabidiol. Here we have provided a novel model that will complement existing zebrafish models and will expand on the potential use of zebrafish larvae for studying both nociception and new analgesics.

PMID: 28935439 [PubMed – as supplied by publisher]

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[Delta-9-tetrahydrocannabinol-cannabidiol in the treatment of spasticity in chronic spinal cord injury: a clinical experience].

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[Delta-9-tetrahydrocannabinol-cannabidiol in the treatment of spasticity in chronic spinal cord injury: a clinical experience].

Rev Neurol. 2017 Oct 01;65(7):295-302

Authors: Grao-Castellote C, Torralba-Collados F, Gonzalez LM, Giner-Pascual M

Abstract
INTRODUCTION: Spasticity in chronic spinal cord injury is a condition that can have negative repercussions on the patient’s quality of life. Its treatment is complex and sometimes the outcome is insufficient. Cannabinoids have recently been used in multiple sclerosis to successfully treat spasticity that is refractory to other therapies.
AIM: To quantify the clinical response of a group of patients with spastic chronic spinal cord injury to the orally administered drug delta-9-tetrahydrocannabinol-cannabidiol (Sativex ®) as medication for use in special situations.
PATIENTS AND METHODS: The research consists of a six-month observational study in patients with chronic spinal cord injuries with refractory spasticity. The variables collected were: modified Ashworth scale, Penn spasm frequency scale, Numeric Rating Scale, and Visual Analogue Scale for pain. Additionally, clinical variables and side effects of the treatment were also collected.
RESULTS: Fifteen patients took part in this study. A significant improvement was observed on three of the scales recorded: modified Ashworth scale (z = -2.97; p = 0.003), Penn spasm frequency scale (z = -2.76; p = 0.006) and Numeric Rating Scale (z = -3.21; p = 0.001). The use of the drug was withdrawn in two patients due to side effects.
CONCLUSIONS: Sativex can be considered an alternative in patients with spasticity associated with chronic spinal cord injury for whom other therapeutic measures have been insufficient. Further studies need to be conducted before the use of this drug can be recommended and so as to define a complete profile of its long-term side effects.

PMID: 28929471 [PubMed – in process]

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Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as Adjunctive Therapy in Advanced Cancer Patients With Chronic Uncontrolled Pain.

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Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as Adjunctive Therapy in Advanced Cancer Patients With Chronic Uncontrolled Pain.

J Pain Symptom Manage. 2017 Sep 15;:

Authors: Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Kornyeyeva E, Fallon MT

Abstract
CONTEXT: Prior phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.
OBJECTIVE: To assess adjunctive nabiximols (Sativex(®)), an extract of Cannabis sativa containing two potentially therapeutic cannabinoids (Δ9-tetrahydrocannabinol [27 mg/mL] and cannabidiol [25mg/mL]), in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.
METHODS: Phase 3, double-blind, randomized, placebo-controlled trial in patients with advanced cancer and average pain NRS scores ≥ 4 and ≤ 8 despite optimized opioid therapy. Patients randomized to nabiximols (n=199) or placebo (n=198) self-titrated study medications over a 2-week period, followed by a 3-week treatment period at the titrated dose.
RESULTS: Median percent improvements in average pain NRS score from baseline to end of treatment in the nabiximols and placebo groups were 10.7% versus 4.5% (p=0.0854) in the ITT population (primary variable) and 15.5% versus 6.3% (p=0.0378) in the Per Protocol population. Nabiximols was statistically superior to placebo on two of three quality-of-life instruments at week 3 and on all three at week 5. In exploratory post hoc analyses, US patients, but not patients from the rest of the world (ROW), experienced significant benefits from nabiximols on multiple secondary endpoints. Possible contributing factors to differences in nabiximols efficacy include: 1) the US participants received lower doses of opioids at baseline than the ROW; and 2) the subgroups had different distribution of cancer pain types, which may have been related to differences in pathophysiology of pain. The safety profile of nabiximols was consistent with earlier studies.
CONCLUSIONS: Although not superior to placebo on the primary efficacy endpoint, nabiximols had benefits on multiple secondary endpoints, particularly in US patients. Nabiximols might have utility in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy.

PMID: 28923526 [PubMed – as supplied by publisher]

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Cannabis constituent synergy in a mouse neuropathic pain model.

Category : Dolor

Cannabis constituent synergy in a mouse neuropathic pain model.

Pain. 2017 Sep 01;:

Authors: Casey SL, Atwal N, Vaughan CW

Abstract
Cannabis and its psychoactive constituent Δ9-tetrahydrocannabinol (THC) have efficacy against neuropathic pain however, this is hampered by their side-effects. It has been suggested that co-administration with another major constituent cannabidiol (CBD) might enhance the analgesic actions of THC and minimise its deleterious side-effects. We examined the basis for this phytocannabinoid interaction in a mouse chronic constriction injury (CCI) model of neuropathic pain. Acute systemic administration of THC dose-dependently reduced CCI-induced mechanical and cold allodynia, but also produced motor incoordination, catalepsy and sedation. CBD produced a lesser dose-dependent reduction in allodynia, but did not produce the cannabinoid side-effects. When co-administered in a fixed ratio, THC and CBD produced a biphasic dose-dependent reduction in allodynia. At low doses, the THC:CBD combination displayed a 200-fold increase in anti-allodynic potency, but had lower efficacy compared to that predicted for an additive drug interaction. By contrast, high THC:CBD doses had lower potency, but greater anti-allodynic efficacy compared to that predicted for an additive interaction. Only the high dose THC:CBD anti-allodynia was associated with cannabinoid side-effects and these were similar to those of THC alone. Unlike THC, the low dose THC:CBD anti-allodynia was not cannabinoid receptor mediated. These findings demonstrate that CBD synergistically enhances the pain relieving actions of THC in an animal neuropathic pain model, but has little impact on the THC-induced side-effects. This suggests that low dose THC:CBD combination treatment has potential in the treatment of neuropathic pain.

PMID: 28885457 [PubMed – as supplied by publisher]

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Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

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Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

Pain. 2017 Sep 01;:

Authors: Philpott HT, O’Brien M, McDougall JJ

Abstract
Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a non-euphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine if CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. OA was induced in male Wistar rats (150-175g) by intra-articular injection of sodium monoiodoacetate (MIA; 3mg). On day 14 (end stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology while pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 post-MIA. Joint nerve myelination was calculated by G-ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100-300μg) were assessed. In end stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (p<0.0001; n=8). Acute, transient joint inflammation was reduced by local CBD treatment (p<0.0001; n=6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (p<0.0001; n=8), and was also found to be neuroprotective (p<0.05; n=6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

PMID: 28885454 [PubMed – as supplied by publisher]

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A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity.

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A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity.

BMJ Open. 2017 Sep 07;7(9):e016843

Authors: Marinelli L, Balestrino M, Mori L, Puce L, Rosa GM, Giorello L, Currà A, Fattapposta F, Serrati C, Gandolfo C, Abbruzzese G, Trompetto C

Abstract
INTRODUCTION: Stroke is the most disabling neurological disorder and often causes spasticity. Transmucosal cannabinoids (tetrahydrocannabinol and cannabidiol (THC:CBD), Sativex) is currently available to treat spasticity-associated symptoms in patients with multiple sclerosis. Cannabinoids are being considered useful also in the treatment of pain, nausea and epilepsy, but may bear and increased risk for cardiovascular events. Spasticity is often assessed with subjective and clinical rating scales, which are unable to measure the increased excitability of the monosynaptic reflex, considered the hallmark of spasticity. The neurophysiological assessment of the stretch reflex provides a precise and objective method to measure spasticity. We propose a novel study to understand if Sativex could be useful in reducing spasticity in stroke survivors and investigating tolerability and safety by accurate cardiovascular monitoring.
METHODS AND ANALYSIS: We will recruit 50 patients with spasticity following stroke to take THC:CBD in a double-blind placebo-controlled cross-over study. Spasticity will be assessed with a numeric rating scale for spasticity, the modified Ashworth scale and with the electromyographical recording of the stretch reflex. The cardiovascular risk will be assessed prior to inclusion. Blood pressure, heart rate, number of daily spasms, bladder function, sleep disruption and adverse events will be monitored throughout the study. A mixed-model analysis of variance will be used to compare the stretch reflex amplitude between the time points; semiquantitative measures will be compared using the Mann-Whitney test (THC:CBD vs placebo) and Wilcoxon test (baseline vs treatment).
ETHICS AND DISSEMINATION: The study was registered on the EudraCT database with number 2016-001034-10 and approved by both the Italian Medicines Agency (Agenzia Italiana del Farmaco) and local Ethics Committee ‘Comitato Etico Regionale della Liguria’. Data will be made anonymous and uploaded to a open access repository. Results will be disseminated by presentations at national and international conferences and by publication in journals of clinical neuroscience and neurology.

PMID: 28882919 [PubMed – in process]

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A selective review of medical cannabis in cancer pain management.

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A selective review of medical cannabis in cancer pain management.

Ann Palliat Med. 2017 Aug 23;:

Authors: Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, Chow E, O’Hearn S

Abstract
Insufficient management of cancer-associated chronic and neuropathic pain adversely affects patient quality of life. Patients who do not respond well to opioid analgesics, or have severe side effects from the use of traditional analgesics are in need of alternative therapeutic op-tions. Anecdotal evidence suggests that medical cannabis has potential to effectively manage pain in this patient population. This review presents a selection of representative clinical studies, from small pilot studies conducted in 1975, to double-blind placebo-controlled trials conducted in 2014 that evaluated the efficacy of cannabinoid-based therapies containing tetrahydrocannabinol (THC) and cannabidiol (CBD) for reducing cancer-associated pain. A review of literature published on Medline between 1975 and 2017 identified five clinical studies that evaluated the effect of THC or CBD on controlling cancer pain, which have been reviewed and summarised. Five studies that evaluated THC oil capsules, THC:CBD oromucosal spray (nabiximols), or THC oromucosal sprays found some evidence of cancer pain reduction associated with these therapies. A variety of doses ranging from 2.7-43.2 mg/day THC and 0-40 mg/day CBD were administered. Higher doses of THC were correlated with increased pain relief in some studies. One study found that significant pain relief was achieved in doses as low as 2.7-10.8 mg THC in combination with 2.5-10.0 mg CBD, but there was conflicting evidence on whether higher doses provide superior pain relief. Some reported side effects include drowsiness, hypotension, mental clouding, and nausea and vomiting. There is evidence suggesting that medical cannabis reduces chronic or neu-ropathic pain in advanced cancer patients. However, the results of many studies lacked statistical power, in some cases due to limited number of study subjects. Therefore, there is a need for the conduct of further double-blind, placebo-controlled clinical trials with large sample sizes in order to establish the optimal dosage and efficacy of different cannabis-based therapies.

PMID: 28866904 [PubMed – as supplied by publisher]

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